Getting to the root of scales, feather and hair: As deep as odontodes?

While every jawed vertebrate, or its recent ancestor, possesses teeth, skin appendages are characteristic of the living clades: skin denticles (odontodes) in chondrichthyans, dermal scales in teleosts, ducted multicellular glands in amphibians, epidermal scales in squamates, feathers in birds and hair-gland complexes in mammals, all of them showing a dense periodic patterning. While the odontode origin of teleost scales is generally accepted, the origin of both feather and hair is still debated. They appear long before mammals and birds, at least in the Jurassic in mammaliaforms and in ornithodires (pterosaurs and dinosaurs), and are contemporary to scales of early squamates. Epidermal scales might have appeared several times in evolution, and basal amniotes could not have developed a scaled dry integument, as the function of hair follicle requires its association with glands. In areas such as amnion, cornea or plantar pads, the formation of feather and hair is prevented early in embryogenesis, but can be easily reverted by playing with the Wnt/BMP/Shh pathways, which both imply the plasticity and the default competence of ectoderm. Conserved ectodermal/mesenchymal signalling pathways lead to placode formation, while later the crosstalk differs, as well as the final performing tissue(s): both epidermis and dermis for teeth and odontodes, mostly dermis for teleosts scales and only epidermis for squamate scale, feather and hair. We therefore suggest that tooth, dermal scale, epidermal scale, feather and hair evolved in parallel from a shared placode/dermal cell unit, which was present in a common ancestor, an early vertebrate gnathostome with odontodes, ca. 420 million years ago.

The Trichohyalin-Like Protein Scaffoldin Is Expressed in the Multilayered Periderm during Development of Avian Beak and Egg Tooth.

Scaffoldin, an S100 fused-type protein (SFTP) with high amino acid sequence similarity to the mammalian hair follicle protein trichohyalin, has been identified in reptiles and birds, but its functions are not yet fully understood. Here, we investigated the expression pattern of scaffoldin and cornulin, a related SFTP, in the developing beaks of birds. We determined the mRNA levels of both SFTPs by reverse transcription polymerase chain reaction (RT-PCR) in the beak and other ectodermal tissues of chicken (Gallus gallus) and quail (Coturnix japonica) embryos. Immunohistochemical staining was performed to localize scaffoldin in tissues. Scaffoldin and cornulin were expressed in the beak and, at lower levels, in other embryonic tissues of both chickens and quails. Immunohistochemistry revealed scaffoldin in the peridermal compartment of the egg tooth, a transitory cornified protuberance (caruncle) on the upper beak which breaks the eggshell during hatching. Furthermore, scaffoldin marked a multilayered peridermal structure on the lower beak. The results of this study suggest that scaffoldin plays an evolutionarily conserved role in the development of the avian beak with a particular function in the morphogenesis of the egg tooth.

TGF-ß Family Signaling in Epithelial Differentiation and Epithelial-Mesenchymal Transition.

Epithelia exist in the animal body since the onset of embryonic development; they generate tissue barriers and specify organs and glands. Through epithelial-mesenchymal transitions (EMTs), epithelia generate mesenchymal cells that form new tissues and promote healing or disease manifestation when epithelial homeostasis is challenged physiologically or pathologically. Transforming growth factor-ßs (TGF-ßs), activins, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs) have been implicated in the regulation of epithelial differentiation. These TGF-ß family ligands are expressed and secreted at sites where the epithelium interacts with the mesenchyme and provide paracrine queues from the mesenchyme to the neighboring epithelium, helping the specification of differentiated epithelial cell types within an organ. TGF-ß ligands signal via Smads and cooperating kinase pathways and control the expression or activities of key transcription factors that promote either epithelial differentiation or mesenchymal transitions. In this review, we discuss evidence that illustrates how TGF-ß family ligands contribute to epithelial differentiation and induce mesenchymal transitions, by focusing on the embryonic ectoderm and tissues that form the external mammalian body lining.

Bones, feathers, teeth and coat markings: a unified model.

A first necessary criterion to be met by any model for pattern formation is that it must be able to reproduce the patterns it purports to model. The above examples show how simple ideas from self-organisation can produce spatial patterns of varying complexity that are consistent with those observed experimentally. Second, the model must be consistent with the results of experimental manipulation. Third, the model must make experimentally testable predictions. In this way, a mathematical model can help to elucidate the underlying biochemical and biophysical mechanisms of pattern formation. I have tried to illustrate these ideas with the above examples. These examples also show the breadth of patterning phenomena that can be captured by these models. In animal coat markings, the patterns are laid down simultaneously. In limb development, the skeletal elements are laid down sequentially. The application to feather germ formation illustrates complex sequential regular pattern formation, while the application to tooth primordium formation illustrates sequential irregular pattern formation. Many other patterning phenomena have been studied (see, for example, ref. 7). Pattern formation is one of the central issues in developmental biology and intense interdisciplinary research involving experimentalists and theoreticians is beginning to help us understand how this phenomenon occurs. A detailed understanding of normal development is a necessary first step to the understanding of abnormal development and, hopefully, will help medical science combat developmental defects.

Dinosaur's feather and chicken's tooth? Tissue engineering of the integument.

The integument forms the interface between animals and the environment. During evolution, diverse integument and integument appendages have evolved to adapt animals to different niches. The formation of these different integument forms is based on the acquisition of novel developmental mechanisms. This is the way Nature does her tissue/organ engineering and experiments. To do tissue engineering of the integument in the new century for medical applications, we need to learn more principles from developmental and evolutionary studies. A novel diagram showing the evolution and development of integument complexity is presented, and the molecular pathways involved discussed. We then discuss two examples in which the gain and loss of appendages are modulated: transformation of avian scale epidermis into feathers with mutated beta catenin, and induction of chicken tooth like appendages with FGF, BMP and feather mesenchyme.

Genetic basis of skin appendage development.

Morphogenesis of hair follicles, teeth, and mammary glands depends on inductive epithelial-mesenchymal interactions mediated by a conserved set of signalling molecules. The early development of different skin appendages is remarkably similar. Initiation of organogenesis is marked by the appearance of a local epithelial thickening, a placode, which subsequently invaginates to produce a bud. These early developmental stages require many of the same genes and signalling circuits and consequently alterations in them often cause similar phenotypes in several skin appendages. After the bud stage, these organs adopt diverse patterns of epithelial growth, reflected in the usage of more divergent genes in each.

Engineering stem cells into organs: topobiological transformations demonstrated by beak, feather, and other ectodermal organ morphogenesis.

To accomplish regenerative medicine, several critical issues in stem cell biology have to be solved, including the identification of sources, the expanding population, building them into organs, and assimilating them to the host. Although many stem cells can now differentiate along certain lineages, knowledge on how to use them to build organs lags behind. Here we focus on topobiological events that bridge this gap, for example, the regulation of number, size, axes, shape, arrangement, and architecture during organogenesis. Rather than reviewing detail molecular pathways known to disrupt organogenesis when perturbed, we highlight conceptual questions at the topobiological level and ask how cellular and molecular mechanisms can work to explain these phenomena. The avian integument is used as the Rosetta stone because the molecular activities are linked to organ forms that are visually apparent and have functional consequences during evolution with fossil records and extant diversity. For example, we show that feather pattern formation is the equilibrium of stochastic interactions among multiple activators and inhibitors. Although morphogens and receptors are coded by the genome, the result is based on the summed physical-chemical properties on the whole cell's surface and is self-organizing. For another example, we show that developing chicken and duck beaks contain differently configured localized growth zones (LoGZs) and can modulate chicken beaks to phenocopy diverse avian beaks in nature by altering the position, number, size, and duration of LoGZs. Different organs have their unique topology and we also discuss shaping mechanisms of liver and different ways of branching morphogenesis. Multi-primordium organs (e.g., feathers, hairs, and teeth) have additional topographic specificities across the body surface, an appendage field, or within an appendage. Promises and problems in reconstitute feather/hair follicles and other organs are discussed. Finally, simple modification at the topobiological level may lead to novel morphology for natural selection at the evolution level.

Mechanisms of ectodermal organogenesis.

All ectodermal organs, e.g. hair, teeth, and many exocrine glands, originate from two adjacent tissue layers: the epithelium and the mesenchyme. Similar sequential and reciprocal interactions between the epithelium and mesenchyme regulate the early steps of development in all ectodermal organs. Generally, the mesenchyme provides the first instructive signal, which is followed by the formation of the epithelial placode, an early signaling center. The placode buds into or out of the mesenchyme, and subsequent proliferation, cell movements, and differentiation of the epithelium and mesenchyme contribute to morphogenesis. The molecular signals regulating organogenesis, such as molecules in the FGF, TGFbeta, Wnt, and hedgehog families, regulate the development of all ectodermal appendages repeatedly during advancing morphogenesis and differentiation. In addition, signaling by ectodysplasin, a recently identified member of the TNF family, and its receptor Edar is required for ectodermal organ development across vertebrate species. Here the current knowledge on the molecular regulation of the initiation, placode formation, and morphogenesis of ectodermal organs is discussed with emphasis on feathers, hair, and teeth.

Adaptation to the sky: Defining the feather with integument fossils from mesozoic China and experimental evidence from molecular laboratories.

In this special issue on the Evo-Devo of amniote integuments, Alibardi has discussed the adaptation of the integument to the land. Here we will discuss the adaptation to the sky. We first review a series of fossil discoveries representing intermediate forms of feathers or feather-like appendages from dinosaurs and Mesozoic birds from the Jehol Biota of China. We then discuss the molecular and developmental biological experiments using chicken integuments as the model. Feather forms can be modulated using retrovirus mediated gene mis-expression that mimics those found in nature today and in the evolutionary past. The molecular conversions among different types of integument appendages (feather, scale, tooth) are discussed. From this evidence, we recognize that not all organisms with feathers are birds, and that not all skin appendages with hierarchical branches are feathers. We develop a set of criteria for true avian feathers: 1) possessing actively proliferating cells in the proximal follicle for proximo-distal growth mode; 2) forming hierarchical branches of rachis, barbs, and barbules, with barbs formed by differential cell death and bilaterally or radially symmetric; 3) having a follicle structure, with mesenchyme core during development; 4) when mature, consisting of epithelia without mesenchyme core and with two sides of the vane facing the previous basal and supra-basal layers, respectively; and 5) having stem cells and dermal papilla in the follicle and hence the ability to molt and regenerate. A model of feather evolution from feather bud --> barbs --> barbules --> rachis is presented, which is opposite to the old view of scale plate --> rachis --> barbs --> barbules (Regal, '75; Q Rev Biol 50:35).